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HIV, the virus that causes AIDS can be grouped into two families: HIV-1 and HIV 2. The origins of HIV-2 have been established as cross species transmission of a virus infecting a distinct monkey species called Simian immune deficiency virus, to human populations. This dissertation analyses current research around the origins of HIV-1 specifically the strains responsible for the majority of infections worldwide, termed group M. Research has shown that group M has originated due to cross species transmission of a Simian immune deficiency virus from a common chimpanzee species in central Africa. Genetic comparisons as well as comparisons of gene organisation support these findings and also suggest that the last common ancestor of this HIV-1 group existed between 1915 and 1941. I also a focus on the history of the HIV/AIDS discovery as well as theories explaining the cross species transmission, such as monkey to human, blood to blood transmission and an explanation of theories, explaining how HIV has become so diverse, in addition to the changes in infection rates of different HIV-1 groups.
Phylogenetic Comparisons and similarities in gene organisation between SIVcpz in Pan troglodytes troglodytes and HIV-1 (specifically group M) show that they are closely related, suggesting HIV-1 group M originated due to transmission of SIVcpz from Pan troglodytes troglodytes, dating the last common ancestor between 1915-1941. Group M, responsible for the world wide pandemic, like other HIV-1 strains is likely to have arisen due to consumption or blood to blood transmission (hunter theory) of bushmeat from Pan troglodytes troglodytes. Evidence also supports this theory for the establishment of other zoonotic groups of HIV-1, specifically N and O. Research elucidates to a gorilla origin for the HIV-1 P strain, discovered in 2009 in a female of Cameroonian origin. Throughout this dissertation I discuss the history of the HIV-1 pandemic, from its discovery, theories of its origin, including, the contaminated OPV theory, theories explaining its spread such as colonialism, development in infrastructure and the heart of darkness theory in addition to the most supported bushmeat/hunter theory. Also discussed are the origins of HIV-1 group P and the differential frequency of HIV-1 group infections.
Two major lineages of the retrovirus, HIV, cause AIDS, HIV-1 and HIV-2 (Gao, Bailes et al. 1999). The origins of HIV-2, much less common and generally restricted to western Africa, have been established as a zoonosis of SIVsm from sooty mangabeys to the human population (Gao, Bailes et al. 1999, Lemey, Pybus et al. 2003). A wealth of phylogenetic, viral protein sequence similarity and genome similarity studies support these conclusions as well as several epidemiological studies (Gao, Bailes et al. 1999, Bartolo, Rocha et al. 2009). The origins of HIV-1 have also been established (Gao, Bailes et al. 1999, Sharp and Hahn 2011). HIV-1 is responsible for the majority of AIDS cases across the globe and due to high mutation rates during replication of the RNA genome as well as founder effects, this has resulted in the development of genetically distinct subtypes.
HIV-1 is categorised into four groups, group M (major group) is believed to be responsible for 90 percent of HIV/AIDS cases worldwide and therefore will be the major focus of this dissertation (Hemelaar, Gouws et al. 2006). Groups N, O and recently P have also been established, these groups represent separate transmissions of SIV's to humans (Hillis 2000, Sauter, Hue et al. 2011). The main group, group M is further divided into subtypes based on epidemiology and sequence differences, group M also encapsulates CRF's, circulating recombinant forms, the result of co-infection, recombination and spread of more than one subtype, those within the HIV-1 Group M domain (Vidal, Peeters et al. 2000, Hemelaar, Gouws et al. 2006). Figure one shows the global distribution of HIV-1 Group M subtypes A-K and CRF's along with their proposed geographical migration routes.
Figure 1. Proposed migration routes for the spread of HIV infection and global prevalence of HIV-1 groups, subtypes and CRF's. Figure from: http://www.medscape.com/viewarticle/760844_4 [last accessed 1st march 2013]
Discovering HIV: A historical perspective
What we have now come to know as HIV-1 was first identified in groups of male homosexuals and intravenous drug users in cities of the United States. In health centres clusters of gay men were presenting with various symptoms, primarily pneumocystis pneumonia, cytomegalo virus, lymphadenopathy, kaposi's sarcoma and candidiasis (Gallo and Montagnier 2003). A report in 1981 for the center of disease control highlighted several cases of pneumocystis pneumonia in homosexual men living in Los Angeles (Gallo and Montagnier 2003). The sharp increase in case number led to the adopting of the term GRID or gay related immune deficiency, what we call AIDS today (Gallo and Montagnier 2003).
Haemophiliacs were also identified as a susceptible risk group in the early 1980's, and a race between American and Parisian scientists was initialised to try to identify the causative agent. The joint efforts of the laboratories of Robert Gallo at the national institute of health in the US and Luc Montagnier at the Pasteur institute in Paris led to the isolation of the virus and demonstration that the virus caused AIDS (Gallo and Montagnier 2003). A debate ensued between the two scientists over the name of the virus settling on a compromise, HIV. Although the virus was identified in 1983, pre existing samples from the early 20th century show that HIV has infected humans, historically (Zhu, Korber et al. 1998). Specifically a sample taken from an African man who died in 1959 of a mysterious illness, tested positive for HIV. Epidemiological studies suggest that HIV reached pandemic proportions around 1969 (Zhu, Korber et al. 1998, Hillis 2000, Walker, Grassly et al. 2004) . Figure two shown below illustrates the time encapsulating the discovery of what we now know as HIV, important events and their progression.
Figure 2. Timeline of important events surrounding the discovery/ identification of HIV and AIDS.
Tackling theories, bushmeat and epidemic emergence
Numerous theories have been proposed in an attempt to explain the origin of HIV-1, responsible for the world wide pandemic. One such theory suggested that the virus originated from contaminated oral polio vaccine (Hooper 2001). Supporters of the theory argue that chimpanzees in the Kisangani region of the Democratic republic of Congo were infected with SIVcpz were used to culture OPV (in vivo) during the WHO attempts to eradicate polio myelitis across the globe (Worobey, Santiago et al. 2004). They held the opinion that the vaccine had been contaminated with SIVcpz and that this was the source for the current HIV-1/AIDS pandemic. Research in 2004 refuting the theory, finally put this theory to rest (Worobey, Santiago et al. 2004). By molecularly characterising and surveying chimpanzees in the Kisangani region researchers were eventually able to isolate SIVcpz viral RNA from the faeces of endemic chimpanzees, non-invasively. Genome and RNA analysis showed that the endemic SIVcpz strain was highly divergent from HIV-1, coupled with the wealth of data suggesting that HIV-1 emerged before OPV trials were initiated, the OPV theory can now be conclusively discounted as an explanation for the origin of HIV-1 and specifically HIV-1 group M (Worobey, Santiago et al. 2004). Figure three shows a constructed phylogenetic tree for Nef/gp41 sequences, illustrating that the SIVcpz DRC1 strain is distinct and highly divergent from the SIVcpz implicated in resultant HIV-1 infections.
Figure 3. Nef/gp41 Phylogenetic relatedness tree comparisons of SIV's and HIV-1.
(Worobey, Santiago et al. 2004)
Other theories include the apparent splicing of Visna and HTLV-1 virus by the US military for population control of those with African descent (Klonoff and Landrine 1999, Libbey 2003). Some religious groups argue that HIV is a form of divine retribution sent by god to punish those most promiscuous (Somlai, Heckman et al. 1997). Such theories have no scientific evidence to support them have since been discredited, just like the theory that HIV does not cause AIDS (Blattner, Gallo et al. 1988).
The most plausible theory for the origins of the four HIV-1 groups is that cross species transmission events of a similar virus, either SIVgor or SIVcpz (depending on the group) from primates, infected human populations (Hillis 2000, Peeters, Courgnaud et al. 2002, Rambaut, Posada et al. 2004, Sharp and Hahn 2011). However the question of how the virus came to enter the human population and its initial mode of transmission has not yet been fully ascertained. Currently the majority of evidence suggests bushmeat as the source of SIV transmission into the human population for the majority of current HIV-1 cases (Hillis 2000, Peeters, Courgnaud et al. 2002, Rambaut, Posada et al. 2004, Sharp and Hahn 2011). Bushmeat is the meat of wild animal's killed for food. Primates such as monkeys and gorillas in western and central Africa are often hunted and are still a source of SIV. It is thought that consumption of bushmeat coupled with blood to blood infection from butchery is the major source of SIV zoonosis into the human population resulting in HIV-1 groups M,N and O (Peeters, Courgnaud et al. 2002). A study in 2002 in Cameroon demonstrated that around 20 percent of primate bushmeat was infected with SIV, suggesting that Bushmeat is the primary source of SIV infection in humans which can result in HIV (SIVcpz/SIVgor) (Peeters, Courgnaud et al. 2002) .
Another theory that is coupled with the bushmeat or hunter theory is that the wide spread use of syringes by African health officials lead to the rise of HIV. Disposable plastic syringes were used to administer medicines to multiple individuals repetitively, with little sterilisation In between, resulting in HIV emergence around the 1930's (Chitnis, Rawls et al. 2000, Peeters, Courgnaud et al. 2002). This could have resulted in SIV transmissions from person to person, allowing the virus to adapt to the human population, resulting in HIV.
Other hypotheses focus on the emergence of HIV in the human population. They suggest that urbanisation as well as social changes in Africa led to increased transmission and more widespread emergence of HIV. The theory suggests that due to colonisation, formations of cities, towns and a movement away from secular tribes; sexual promiscuity increased (Sharp, Bailes et al. 2001, Peeters, Courgnaud et al. 2002, de Sousa, Mueller et al. 2010). This increase in promiscuity, coupled with new infrastructure and wide spread travel is thought to have led to the widespread emergence of HIV. Phylogenetic analysis by Korber, shows that the origins of HIV-1 groups M and O coincides with the establishment of major colonial cities and infrastructure in central Africa (Korber 2000). Figure four shows the rate of population increase in Kinshasa and bordering Brazzaville during colonialism (1906-1968), the establishment of transport links and cities led to increased migration and settling of families. The population explosion correlates well with the location and date of the proposed HIV-1 origins (Chitnis, Rawls et al. 2000).
Figure 4. Population graph during the colonialism period 1906-1968 in Kinsasha and neighbouring Brazzaville.
Figure from :- (Chitnis, Rawls et al. 2000)
Another theory known as the "Heart of darkness" theory proposed by Amit Chitins et al. (2000) also suggests that HIV emerged due to social and economic changes with respect to colonialism, specifically in French equatorial Africa where harsh, forced labouring conditions were rife, and bushmeat was a common staple food (Chitnis, Rawls et al. 2000). The heart of darkness theory ties in with that of social change and urbanisation, as well as wide spread use of unsterilized needles to administer medicines and vaccines (Chitnis, Rawls et al. 2000, Marx, Alcabes et al. 2001).
Dating the source of HIV-1 transmission
Although HIV-1 was only identified in the 1980's; phylogenetic evidence suggests origins well before then. Indeed, many independent HIV lineages were already circulating in African populations (Zhu, Korber et al. 1998, Vidal, Peeters et al. 2000, Bartolo, Rocha et al. 2009). To reiterate groups M, N and O all represent separate lineages of HIV-1, from SIV infection's in Pan troglodytes troglodytes although the origins of group O have not been fully established and could originate from SIVgor. It is also clear that the first cases of HIV-1 were likely to be in west and central Africa, as a result of sequence comparisons of HIV-1 gag, pol and env genes (Gao, Bailes et al. 1999, Keele, Van Heuverswyn et al. 2006). But when did this occur? Using molecular clock analysis to determine when lineages split, assuming a constant rate of mutation and using the dates of known molecular divergences Korber and colleges showed that the last common ancestor of HIV-1 group M was in existence around 1915-1941 (Hillis 2000, Korber 2000). Analysis of HIV-1 group M, gag and env genes both gave similar results. It is important to note that this date range represents the existence of the last common ancestor and not the date of cross species transmission (Hillis 2000). As David Hills writes about in his article "origins of HIV" this information gives rise to three hypothesis' for initial transmission of HIV -1 group M, the most well supported termed " transmission early" , (see figure five) tying in with the heart of darkness and socio economic and urbanisation theories of HIV origins; Suggesting that political, social and economic changes in central and western Africa accounted for the initial spread of the virus and its diversity in human populations.
Figure 5. Transmission early hypothesis, showing diverging subtypes originating from one original lineage
Figure adapted from :- (Hillis 2000)
The origins of the HIV-1 pandemic- Group M
HIV-1 Group M is responsible for the majority of HIV/AIDS cases across the world, HIV-2 is mainly restricted to west and central Africa (Gao, Bailes et al. 1999). It therefore necessary to focus on the origins of HIV-1 Group M when describing the pandemic, as well as the individual zoonotic event resulting in its establishment. Group M encapsulates several subtypes of HIV, including many clades endemic to distinct geographical populations, as well as circulating recombinant forms, established due to recombination of viruses of different subtypes in vivo. However it is clear that all of these clades/subtypes emerged from one ancestral strain of HIV-1 (Vidal, Peeters et al. 2000).
We now know that pandemic HIV-1 is of chimpanzee origin. (Gao, Bailes et al. 1999, Sharp and Hahn 2011). Thanks to non invasive ape population studies in recent years, determining SIVcpz infection in Pan troglodytes schweinfurthii in eastern Africa, and Pan troglodytes troglodytes in central Africa, it has now been established beyond reasonable doubt that the source or reservoir of HIV-1 group M is the SIVcpz infected chimpanzee species Pan troglodytes troglodytes. Studies of antibodies in primate faeces have made this all possible as well as linking Pan troglodytes troglodytes in southern Cameroon to the source of the pandemic (Keele, Van Heuverswyn et al. 2006).
Pan troglodytes schweinfurthii SIVcpz virus shows considerable genetic diversity from the virus found in Pan troglodytes troglodytes approximately 30-50 percent difference in protein sequences of gag pol and env genes, and considerable diversity from HIV-1 groups M, N and O compared with SIV infected Pan troglodytes troglodytes (Gao, Bailes et al. 1999, Hillis 2000, Santiago, Rodenburg et al. 2002, Sharp and Hahn 2011). Pandemic HIV-1 infections are only closely related to SIVcpz in Pan troglodytes troglodytes thus suggesting that this is the species of chimpanzee responsible for the current world wide pandemic. SIV infected Pan troglodytes troglodytes in central Africa, and Pan troglodytes schweinfurthii, eastern Africa, allow determination of the geographic source of HIV-1.
Group P, the mystery of frequency and tetherin.
In the last few years a new lineage of HIV-1 has become apparent. Group P, detected in a small number of patients, was found by HIV virologists in a Cameroonian female (Plantier, Leoz et al. 2009). Upon isolation of the virus and phylogenetic analysis researchers found that unlike HIV-1 M,N and O, the P group is most similar to SIVgor than SIVcpz (Plantier, Leoz et al. 2009), suggesting a gorilla origin for the virus. Data suggests that HIV-1 group P entered the human population between 1845 and 1989 (Gupta and Towers 2009). What has still remained a mystery is the fact that HIV-1 N, O and P groups are considerably less prevalent than group M across the globe, when comparably, ancestry dating differences are insignificant. This suggests that group M is more infectious, or that it has selective advantages over the N, O and P groups (Gupta and Towers 2009, Sauter, Hue et al. 2011).
Tetherin, a protein induced by the human interferon response, works to prevent the release of HIV-1. Several proposed mechanisms have been put forward to explain these interactions (Gupta and Towers 2009). Tetherin's may hold the key to explaining the low global frequency of HIV-1 infections in subtypes N,O and P. Research by Sauter and colleagues in 2009 detailed that HIV-1 group M had adapted its Vpu protein allowing successful release of HIV virions from infected cells. This adaptation allowed the Vpu protein to antagonize tetherin and perhaps plays a large role in explaining why HIV-1 group M is so prevalent (Gupta and Towers 2009). Research into groups O and P suggest that there viruses could not antagonize tetherin successfully, possibly helping to explain the lower prevalence of these infections globally when compared with group M (Gupta and Towers 2009). In research into group N and tetherin's research was less conclusive. Due to the rarity of group N infection, only three individuals tetherin activity was tested, In one individual tetherin was antagonised well, in the other two there was little antagonistic activity (Gupta and Towers 2009). Research published today (20/3/2013) has shown that only changes in the transmembrane domain of HIV-1 Vpu is "sufficient to confer anti-tetherin activity to SIVcpz and SIVgor Vpu proteins", (Kluge, Sauter et al. 2013).
An area in which there has been little research into is the genetics of the tetherin protein. Due to the low frequency of group N, O and P infections, it is plausible that some individuals with these infections may have amino acid changes or mutations in there tetherin protein which make them more susceptible to group N, O or P infection. This hypothesis provides an explanation for the largely differing infection rates between the groups.
The origins of the HIV-1 Pandemic started due to cross infection of SIVcpz from Pan troglodytes troglodytes , in central Africa, resulting in the establishment of HIV-1 group M (pandemic strain) (Gao, Bailes et al. 1999, Sharp and Hahn 2011). This zoonosis event is likely to have occurred due to consumption, or blood to blood (hunter theory) transmission from bushmeat (Pan troglodytes troglodytes) to humans (Peeters, Courgnaud et al. 2002). HIV-1 groups M, N, O and P represent four independent zoonotic events. It is clear that over time the human SIVcpz infection adapted to become HIV, disease-causing in the human population. In French Equatorial Africa colonialism, contaminated needles, increased promiscuity and better infrastructure may have also been responsible for the spread of HIV-1.
Phylogenetic data, and standardized sequence data show that the common ancestor to the SIVcpz, responsible for the HIV-1 pandemic strain (M) originated between 1915 and 1941 (Zhu, Korber et al. 1998, Korber 2000).HIV-1 groups N,O and P may have very low frequency of infection / prevalence due to viral protein interactions between them and the human protein tetherin, which works to prevent virion release (Gupta and Towers 2009, Sauter, Hue et al. 2011). As many primate species are infected with SIV there may be concern about the possibility of new zoonosis arising with the potential for new pandemic strains. However host restriction factor's as well as SIV differences in primates coupled with the need for serial passage and adaptive mutation's will provide a functional barrier against future cross species transmissions (Sharp and Hahn 2011).